Unaccustomed physical exercise results in delayed-onset muscle soreness, release of muscle enzymes into the circulation and increased myofibrillar protein breakdown. Eccentric exercise, in which muscles are forced to lengthen as they develop tension, is a particularly potent inducer of these responses. In the initial funding period of this grant, we have characterized eccentric exercise-induced changes in host defense factors in humans, specifically activation of neutrophils and production of the cytokine interleukin-1beta. We found highly significant correlations between these defense mechanisms and the muscular responses. Moreover, these parameters were significantly influenced by age and by dietary vitamin E supplementation. In the next 3 years, we propose to determine if the host defense mechanisms do indeed mediate damage or recovery of muscle by studying the responses of young and old mice to eccentric exercise after interventions that alter in vivo levels of cytokines and neutrophils or alter their biological activity. The responses to be measured include changes in muscle membrane permeability, loss of muscle strength (measured in vitro) and the extent of muscle fiber damage (assessed histochemically). The proposal is intended to help develop an understanding of the mechanisms involved in muscle damage and recovery in response to exercise stress. In addition, these studies may lead to new therapies for injury- or age- related deficits in muscle function.